U.S. Pat. No. 3,773,925 describes and claims the base substance partricin, a heptaene antibiotic produced by the metabolism of a particular strain of Streptomyces aureofaciens and endowed with a high antifungal and antiprotozoal activity.
U.S. Pat. No. 3,780,173 describes and claims the methyl ester of partricin and U.S. Pat. No. 3,961,047 describes and claims alkyl esters of N-alkyl and N-acyl derivatives of partricin. Furthermore, water-soluble complexes of partricin and partricin derivatives with particular surfactant agents are described and claimed in U.S. Pat. Nos. 3,961,048 and 4,017,603. All the above-mentioned derivatives of partricin and water-soluble complexes thereof are systemically less toxic than partricin itself, whilst the anti-infective activity varies from compound to compound, optimum activity being found in the case of partricin methyl ester (USAN mepartricin) which, though substantially less toxic than partricin, has an almost unchanged antiprotozoal activity and is also far more active against pathogenic fungi.
In view of these properties, mepartricin is widely used in clinical practice for the local treatment of vaginal infections. Another partricin derivative of particular interest is the 1:2 w/w mepartricin-sodium lauryl sulphate complex which, while keeping the microbiological characteristics of mepartricin unaltered, has the property of being water-soluble and, as such, can be administered orally for the systemic treatment of various fungal and protozoal infections.
We have now discovered that, apart from an anti-infective activity, partricin and its derivatives are effective in the treatment of prostatic hypertrophy, reducing the glandular dimensions and modifying the hypertrophic picture so as to return the organ to its normal size and appearance. This action, although related to the antibiotic activity, does not depend on this but is particularly due to the chemical structure.
It is an object of the present invention to provide a clinically very efficient method for the treatment of prostatic hypertrophy.
Another object of the present invention is to provide a composition for the treatment of prostatic hypertrophy.
Benign prostatic hypertrophy (BPH) consists in a glandular hyperplasia resulting in the formation of new structures of the prostatic parenchyma and of the periurethral glands. To a certain extent, it can be considered as being a general phenomenon of advanced age which is susceptible of anomalous evolution. According to some authors, the incidence of clinically documented glandular hyperplasia affects approximately 50% of the male population aged between 50 and 60 years and further increases with advancing age.
Moreover, with increased raised life expectancy, it is obvious that the treatment of prostatic hypertrophy is also of growing importance from a social viewpoint since this condition weighs heavily on national health costs and limits working activity due to the particular symptomatology (pollakiuria, strangury, nocturia). The not infrequent occurrence of ascending infections, which further complicate the general picture, it also to be considered.
Hitherto, it can be said that prostatic hypertrophy has best been dealt with surgically rather than medically in view of the uncertainty which still remains with regard to hormonal therapy. This, no doubt, reflects the dualism existing with regard to the pathogenesis of the hypertrophic process, ascribed by some authors to hyperoestrogenism and by others to androgen hyperproduction following hypophysis stimulation.
From the therapeutic point of view, this has entailed the adoption of widely differing methods of treatment and the use of widely differing kinds of substances with not always comparable results. Currently, androgen therapy is no longer used very much because there are potential risks that a possible carcinoma, coexisting in the hyperplastic context, might be neoplastically activated.
Furthermore, treatment with oestrogens, which is still widely used, can induce feminisation processes, as well as testicular atrophy and squamous epithelial hyperplasia of the posterior urethral tract.
Hormonal therapy, besides directly acting on the prostate itself, thus also induces a number of highly undesirable side effects, particularly after prolonged therapy.
This justifies the search for new, non-hormonal substances which are capable of selectively acting on the prostate without interfering with other parenchyma.
Recently, new hypotheses is the field of benign prostatic hypertrophy have been advanced. First, histochemical studies on human material from autopsies showed a significant increase (approximately 80%) of prostatic cholesterol in subjects with BPH or prostatic neoplasia.
It was also observed that, in rats, the prostate synthesises nearly as much cholesterol as the liver, although it lacks a feed-back mechanism similar to that of the liver and, therefore, it is liable to cholesterol surcharge, resulting in glandular congestion with reactive hyperplasia.
Bearing in mind these observations and the fact that partricin derivatives, like other polyene substances or even more so, are endowed with a marked hypocholesterol activity due to the inhibition of reabsorption of the exogenous pool cholesterol at gastrointestinal tract level (see U.S. Patent Application Ser. No. 910,951) an expermental control was carried out to ascertain the activity of the derivatives in question on benign prostatic hypertrophy.
Following a preliminary screening, which demonstrated that practically all partricin derivatives were endowed with a good basic activity, although sometimes accompanied by signs of gastric intolerance, a more detailed clinical study was carried out with mepartricin, which is less toxic and better tolerated by the oral route compounds, due to the necessity of having to carry out a prolonged therapy without causing harmful side effects. Mepartricin, which is not absorbed gastroenterically and, therefore, acts exclusively at a topical level, gave the highest hypocholesterol efficacy.